Acne vulgaris (or simply acne) is a common skin condition affecting an estimated 650 million people, or 9.4% of the population, worldwide. (Vos et al. Lancet, 380(9859):2163-2196, 2012) The condition, characterized by areas of skin with seborrhea, comedones, papules, nodules, pimples, and possible scarring, often occurs in adolescences, but may persists much further into adulthood (James. N Engl J Med, 352(14):1463-1472, 2005).
Adolescence is a period of high social insecurity, and the appearance of and potential scarring from acne often result in psychological issues such as reduced self-esteem, depression, or, in extreme cases, suicide (Goodman. Aust Fam Physician, 35(7):503-504, 2006; Purvis et al. J Paediatr Child Health, 42(12):793-796, 2006).
An immunological reaction to the gram-positive microbe Propionibacterium acnes (P. acnes) is implicated in playing a major role in the initiation of the acute inflammatory response in patients (De Young et al. J Invest Dermatol, 83(5):394-398, 1984; Jappe et al. Br J Derm. 146(2):202-209, 2002). Acne treatments work by reducing sebum production by sebocytes, speeding up cell turnover, fighting bacterial infection, reducing inflammation, or some combination of these strategies. Treatment of acne tends to be long and primarily focuses on the use of retinoids, benzoyl peroxide, and antibacterials—particularly oral tetracyclines and topical clindamycin. In addition to the growing rate in the resistance of P. acnes to these treatments, recently the usefulness of eradication of P. acnes, a commensal bacteria found in most healthy human skin, as a primary target for therapy in acne has been questioned, and instead some are considering a model based on treatment of the inflammatory response to the bacteria (Agak et al. J Invest Dermatol, 2013). Inflammation is clinically associated in late stages of acne with the presence of inflamed papules and pustules and histologically by the presence of cell infiltrates in open comedones (Tanghetti, E. A. J. Clin. and Aesthetic Derm. 6(9):27-35, 2013). In the past decade, new findings have demonstrated the involvement of inflammatory mechanisms as part of the pathogenesis of early acne (Norris, J. F. and et al. Br. J. Dermatol. 118:651-659, 1988) and the evolving view is that acne should be regarded as an inflammatory disease (Stein, L. F. and et al. J. Drugs Dermatol. Suppl 6:s67-s69, 2013). In fact, the skin is an immunologically active organ. Follicular keratinocytes and sebocytes, the main constituents of the pilosebaceous unit, activate the innate immune system by recognizing P. acnes. Both interfollicular and infundibular human keratinocytes and sebocytes can sense the presence of P. acnes as they express functional Toll-like receptor (TLR) 2, TLR4 and CD14, consistent with the role of these cells in innate immunity (Song, P. I. et al. J. Invest Dermatol. 119:424-432, 2002; Selway, J. L. et al. BMC Dermatol. 13:10, 2013; Nagy et al. Microbes and Infection, 8:2195-2205, 2006). In fact, P. acnes, a gram-positive bacteria, may trigger the immune system in early and late acne lesions through the activation of TLR2 by the pathogen associated molecular patterns (PAMPs) such as peptidoglycan (PGN) and Lipoteichoic acid (LTA). Indeed, IL-1a is released by keratinocytes in response to TLR2 activation. Similarly, PGN and LTA cause keratinocyte hypercornification, which is characteristic of acne lesions. It has also been shown that P. acnes induces the secretion of Th1 and proinflammatory cytokines (IFNγ, IL-12, IL-18, IL-8, and IL-1b) in human monocytes, suggesting that P. acnes may activate tissue macrophages that surround pilosebaceous follicles (Sugisaki, H. et al. J. Dermatol. Sci. 55(1):47-52, 2009; Kim, J. Dermatology. 211(3):193-198, 2005). Finally, recent studies have shown that P. acnes stimulated the expression of Th17-related genes, including IL-17A, RORα, RORγ, IL-17RA and triggered the secretion of IL-17 from CD4 T cells (Agak et al. J Invest Dermatol, February 2014 134(2): 366-73). Therefore, because inflammation is present in both early and late acne lesions, anti-inflammatory therapies are proposed as able to clear acne lesions regardless which etiologic factor is involved in the initiation or maintenance of acne lesions.
The usefulness of commercially available purely anti-inflammatory compounds is limited due to safety concerns with respect to the prolonged use of corticosteroids, and retinoids and vitamin D analogs. Additionally anti-inflammatory treatments can have other effects on sebum production, bacterial populations, and skin turnover.
Thus, there remains a need for safer and more efficacious therapies for use in the treatment of acne. A treatment which is safe, efficacious, and anti-inflammatory by a novel pathway that does not have the same safety concerns as current anti-inflammatory treatments would be an inventive addition to acne treatment regimens.